To determine whether diabetes alters chromatin structure in vivo, fluorometric analysis of alkali-induced DNA unwinding was carried out in various tissues of streptozocin-induced diabetic ratsand genetically obese diabetic (dbldb) mice. When zero-order kinetics were used to analyze the data, the percentage of double-stranded DNA (%dsDNA) unwinding in brain, liver, and intestinalepithelium of diabetic rats maintained for 4 wk was significantly reduced compared with vehicle-injected control rats (%dsDNA 0.37 ± 0.05 vs. 0.73 ± 0.02 for brain, 0.59 ± 0.1vs. 0.84 ± 0.02 for liver, and 0.58 ± 0.07 vs. 0.90 ± 0.13 for intestinal epithelium). Insulin treatment of diabetic rats normalized the rate of DNA unwinding in liver (0.82 ± 0.09 %dsDNA/min) and intestinal epithelium (1.05 ± 0.09 %dsDNA/min), but the increase in the unwinding rate of brain DNA (0.51 ± 0.06 %dsDNA/min) did not achieve control values. Similarly, alkali-induced DNA unwinding was significantly slower in brain and liver of db/db mice compared with homozygote controls. When first-order kinetics were used to analyze the data, fractional rate constants of DNA unwinding in brain and liver of diabetic rats or mice were significantly smaller than observed in nondiabetic control animals. The fractional rate constant of DNA unwinding in intestinal epithelium was not altered with diabetes. We conclude that chronic uncontrolled hyperglycemia can alter chromatin structure in vivo.

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